Blues progression: From a dye to a placebo to an Alzheimer’s treatment?

Why are Alzheimer’s drug developers getting the blues? It depends on what’s meant by “getting the blues.”

The field has been plagued by a succession of failures of one experimental drug after another, Stanford drug researcher Jay Rajadas, PhD, tells me, with promising effects shown in early clinical trials disappearing like mist in the morning in crucial large-scale late trials. In response, big pharmaceutical companies have gradually abandoned their onetime obsession with ridding Alzheimer’s patients’ brains of gummy extracellular deposits known as amyloid plaques (they’re composed of a protein called beta-amyloid) that characterize the disease.

Some drug developers are redirecting their focus to another hallmark feature of Alzheimer’s: so-called neurofibrillary tangles. Although they’re aggregates like amyloid plagues, neurofibrillary tangles are formed from a different protein called tau and found inside of nerve cells instead of outside of them. Their presence actually tracks more closely with clinical symptoms of Alzheimer’s than that of amyloid plaques does. Might clearing them, arresting their continuing formation, or preventing their production in the first place be beneficial?

Enter an old workhorse chemical called methylene blue, initially developed as a stain in 1876 but sometimes described as “the first fully synthetic drug used in medicine” because it has seen action both as a dye and as a medicine: for example, in treating infectious diseases and cancer. It’s even served as a placebo: When patients report that their urine has turned bright blue, the doctor reassures them that “this shows the drug is working.”

A recent incarnation of this pharmacological phoenix has been its experimental use as an Alzheimer’s treatment. In 2008, a Phase II clinical trial concluded that a purified form of methylene blue slowed cognitive decline in people with mild to moderate Alzheimer’s disease. But a slightly altered formulation of the compound proved disappointing in the all-important follow-on Phase III trial.

However, about 15 percent of the patients in that study experienced significant, clinically meaningful effects. In addition, a different research team reported — also in mid-2016 — that a single oral dose of methylene blue increased imaging-detected activity in brain areas controlling short-term memory and attention in healthy individuals.

In order to boost methylene blue’s odds of benefiting the vast majority of patients instead of a mere sliver of them, it would help to understand exactly what it’s doing at the molecular level — which no one really knows. It seems pretty clear that methylene blue does impede the aggregation of tau into neurofibrillary tangles. But how?

Here’s how. In a new study published in Scientific Reports, Rajadas and his colleagues show that methylene blue blocks a particular enzyme, MARK4, one of whose jobs is tacking chemical groups called phosphates onto tau molecules — an absolutely key early step in their aggregation into neurofibrillary tangles.

The identification of methylene blue’s likely mechanism of action means drug developers can home in on MARK4 and tweak methylene blue to more perfectly prevent the aggregation of tau clusters that characterize Alzheimer’s disease and other disorders.

A blueprint, as it were, for success.

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